RESUMO
BACKGROUND Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus. Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e. flavonoids) and synthetic compounds (i.e. calcium dobesilate). Although their precise mechanism of action has not been fully established, they are known to improve venous tone, stabilize capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids. OBJECTIVE The aim of this review was to investigate the efficacy of phlebotonics in alleviating the signs, symptoms and severity of haemorrhoidal disease and verify their effect post-haemorrhoidectomy. METHODS Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2011 issue 9, MEDLINE (1950 to September 2011) and EMBASE (1974 to September 2011). Selection criteria: Only randomized controlled trials evaluating the use of phlebotonics in treating haemorrhoidal disease were used. No cross-over or cluster-randomized trials were included for analysis and any trial which had a quasi-random method of allocation was excluded. Data collection and analysis: Two authors independently extracted the data and analyzed the eligibility of the data for inclusion. Disagreements were resolved by meaningful discussion. MAIN RESULTS We considered twenty-four studies for inclusion in the final analysis. Twenty of these studies (enrolling a total of 2344 participants) evaluated the use of phlebotonics versus a control intervention. One of these twenty studies evaluated the use of phlebotonics with a medical intervention and another study with rubber band ligation. AUTHORS' CONCLUSIONS The evidence suggests that there is a potential benefit in using phlebotonics ...
RESUMO
BACKGROUND: Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus (Kumar 2005). Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e. flavonoids) and synthetic compounds (i.e. calcium dobesilate). Although their precise mechanism of action has not been fully established, they are known to improve venous tone, stabilize capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids.Numerous trials assessing the effect of phlebotonics in treating the symptoms and signs of haemorrhoidal disease suggest that there is a potential benefit. OBJECTIVES: The aim of this review was to investigate the efficacy of phlebotonics in alleviating the signs, symptoms and severity of haemorrhoidal disease and verify their effect post-haemorrhoidectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2011 issue 9 , MEDLINE (1950 to September 2011) and EMBASE (1974 to September 2011). SELECTION CRITERIA: Only randomised controlled trials evaluating the use of phlebotonics in treating haemorrhoidal disease were used. No cross-over or cluster-randomized trials were included for analysis and any trial which had a quasi-random method of allocation was excluded. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and analysed the eligibility of the data for inclusion. Disagreements were resolved by meaningful discussion. MAIN RESULTS: We considered twenty-four studies for inclusion in the final analysis. Twenty of these studies (enrolling a total of 2344 participants) evaluated the use of phlebotonics versus a control intervention. One of these twenty studies evaluated the use of phlebotonics with a medical intervention and another study with rubber band ligation.The remaining four studies included two which compared different forms of phlebotonics with each other, one study which evaluated phlebotonics with a medical intervention and one study which compared the use of phlebotonics with infrared photocoagulation. Eight studies were excluded for various reasons including poor methodological quality.Phlebotonics demonstrated a statistically significant beneficial effect for the outcomes of pruritus (OR 0.23; 95% CI 0.07 to 0.79) (P=0.02), bleeding (OR 0.12; 95% CI 0.04 to 0.37) (P=0.0002), bleeding post-haemorrhoidectomy (OR 0.18; 95% 0.06 to 0.58)(P=0.004), discharge and leakage (OR 0.12; 95% CI 0.04 to 0.42) (P=0.0008) and overall symptom improvement (OR 15.99 95% CI 5.97 to 42.84) (P< 0.00001), in comparison with a control intervention. Although beneficial they did not show a statistically significant effect compared with a control intervention for pain (OR 0.11; 95% CI 0.01 to 1.11) (P=0.06), pain scores post-haemorrhoidectomy (SMD -1.04; 95% CI -3.21 to 1.12 ) (P= 0.35) or post-operative analgesic consumption (OR 0.54; 95% CI 0.30 to 0.99)(P=0.05). AUTHORS' CONCLUSIONS: The evidence suggests that there is a potential benefit in using phlebotonics in treating haemorrhoidal disease as well as a benefit in alleviating post-haemorrhoidectomy symptoms. Outcomes such as bleeding and overall symptom improvement show a statistically significant beneficial effect and there were few concerns regarding their overall safety from the evidence presented in the clinical trials.However methodological limitations were encountered. In order to enhance our conclusion further, more robust clinical trials which take into account these limitations will need to be performed in the future.
Assuntos
Flavonoides/uso terapêutico , Hemorroidas/terapia , Hemostáticos/uso terapêutico , Vasoconstritores/uso terapêutico , Dobesilato de Cálcio/uso terapêutico , Diosmina/uso terapêutico , Humanos , Hidroxietilrutosídeo/análogos & derivados , Hidroxietilrutosídeo/uso terapêutico , Ligadura/métodos , Extratos Vegetais , Cuidados Pós-Operatórios , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Mitochondrial encephalomyopathy and lactic acidosis with strokelike episodes (MELAS) is a severe young onset stroke disorder without effective treatment. We have identified a MELAS patient harboring a 13528A-->G mitochondrial DNA (mtDNA) mutation in the Complex I ND5 gene. This mutation was homoplasmic in mtDNA from patient muscle and nearly homoplasmic (99.9%) in blood. Fibroblasts from the patient exhibited decreased mitochondrial membrane potential (Deltapsim) and increased lactate production, consistent with impaired mitochondrial function. Transfer of patient mtDNA to a new nuclear background using transmitochondrial cybrid fusions confirmed the pathogenicity of the 13528A-->G mutation; Complex I-linked respiration and Deltapsim were both significantly reduced in patient mtDNA cybrids compared with controls. Inhibition of the adenine nucleotide translocase or the F1F0-ATPase with bongkrekic acid or oligomycin caused a loss of potential in patient mtDNA cybrid mitochondria, indicating a requirement for glycolytically generated ATP to maintain Deltapsim. This was confirmed by inhibition of glycolysis with 2-deoxy-D-glucose, which caused depletion of ATP and mitochondrial depolarization in patient mtDNA cybrids. These data suggest that in response to impaired respiration due to the mtDNA mutation, mitochondria consume ATP to maintain Deltapsim, representing a potential pathophysiological mechanism in human mitochondrial disease.
Assuntos
Trifosfato de Adenosina/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias Musculares/metabolismo , Encefalomiopatias Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Mutação Puntual , Acidose Láctica/genética , Acidose Láctica/metabolismo , Trifosfato de Adenosina/genética , Adulto , Antibacterianos/farmacologia , Antimetabólitos/farmacologia , Ácido Bongcréquico/farmacologia , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Desoxiglucose/farmacologia , Complexo I de Transporte de Elétrons/genética , Feminino , Fibroblastos/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias Musculares/genética , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Oligomicinas/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/genética , ATPases Translocadoras de Prótons/antagonistas & inibidores , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismoRESUMO
Autocrine and paracrine events regulated by nerve growth factor (NGF) and relevant receptors (low- and high affinity; p75 neurotrophin receptor [p75(NTR)] and TrkA, respectively) seem to play a significant role in prostate carcinogenesis. Studies reveal that p75(NTR) is both a tumor suppressor of growth and a metastasis suppressor of human prostate cancer cells. Furthermore, p75(NTR) is progressively lost during prostate carcinogenesis. An imbalance between p75(NTR) and tropomyosin receptor kinase A (TrkA)-mediated signals may be involved in the progression of prostate cancer through increased proliferation and reduced apoptosis. The antiproliferative and apoptotic effects of GnRH analogs in prostate cancer cells may be mediated by altering the TrkA:p75(NTR) NGF receptor ratio. Administration of NGF induces a reversion of the androgen-independent/androgen receptor-negative prostate cancer cell lines to a less malignant phenotype. Finally, Trk inhibition is a novel, attractive and rational approach for prostate cancer therapy. This review unravels the NGF 'circuitry' in prostate cancinogenesis for relevant pharmacologic manipulation to lead to the development of novel therapeutic agents.
Assuntos
Fator de Crescimento Neural/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Humanos , Masculino , Fator de Crescimento Neural/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismoRESUMO
The mitochondrial diseases encompass a diverse group of disorders that can exhibit various combinations of clinical features. Defects in mitochondrial DNA (mtDNA) have been associated with these diseases, and studies have been able to assign biochemical defects. Deficiencies in mitochondrial oxidative phosphorylation appear to be the main pathogenic factors, although recent studies suggest that other mechanisms are involved. Reactive oxygen species (ROS) generation has been implicated in a wide variety of neurodegenerative diseases, and mitochondrial ROS generation may be an important factor in mitochondrial disease pathogenesis. Altered apoptotic signaling as a consequence of defective mitochondrial function has also been observed in both in vitro and in vivo disease models. Our current understanding of the contribution of these various mechanisms to mitochondrial disease pathophysiology will be discussed.
Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/genética , Mutação/genética , Humanos , Síndrome MELAS/genética , Mitocôndrias/genética , Miopatias Mitocondriais/genética , Fosforilação Oxidativa , Estresse Oxidativo/fisiologiaRESUMO
The authors analyzed the total mitochondrial (mt) genome in 15 patients with classic mitochondrial phenotypes. Novel somatic mtDNA mutations in two patients with chronic progressive external ophthalmoplegia were identified. Total automated mtDNA genome analysis did not reveal other pathogenic mtDNA mutations. The authors conclude that classic mitochondrial phenotypes, including those with adult onset, may occur in the absence of mtDNA mutations. Nuclear gene mutations may be the cause.
Assuntos
Núcleo Celular/genética , DNA Mitocondrial/genética , Doenças Mitocondriais/genética , Mutação , Oftalmoplegia Externa Progressiva Crônica/genética , Fenótipo , Análise Mutacional de DNA , Complexo IV da Cadeia de Transporte de Elétrons/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Fibras Musculares Esqueléticas/química , Fibras Musculares Esqueléticas/enzimologia , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
We identified two novel heteroplasmic mitochondrial DNA point mutations in the gene encoding the ND5 subunit of complex I: a 12770A-->G transition identified in a patient with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and a 13045A-->C transversion in a patient with a MELAS/Leber's hereditary optic neuropathy/Leigh's overlap syndrome. Biochemical analysis of muscle homogenates showed normal or very mildly reduced complex I activity. Histochemistry was normal. Our observations add to the evidence that mitochondrial ND5 protein coding gene mutations frequently associate with the MELAS phenotype, and it highlights the role of complex I dysfunction in MELAS.